The Diversity of T Cell Activation Antigens. Serological Analysis Including Their Expression on Non-T Acute Lymphoblastic Leukemia Cells and B Cell Lines Derived from Adult T Cell Leukemia Patients

1986 ◽  
pp. 351-360
Author(s):  
Yasuo Morishima ◽  
Tomoko Noumi ◽  
Ken-ichi Ohya ◽  
Saburo Mimami ◽  
Masao Okumura ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphoblastic Leukemia ◽  
Cell Leukemia ◽  
Serological Analysis ◽  
Adult T Cell Leukemia ◽  
Activation Antigens

A Systematic Review of Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Engaging an Old Problem With New Solutions

2021 ◽  
pp. 106002802098841
Author(s):  
Zachery Halford ◽  
Carli Coalter ◽  
Vanessa Gresham ◽  
Tabitha Brown
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Phase Iii ◽  
Cytotoxic T Cell ◽  
Bispecific T Cell Engager

Objective: To assess the current literature for blinatumomab in the treatment of adult and pediatric B-cell acute lymphoblastic leukemia (ALL). Data Sources: We conducted a PubMed (inception to December 11, 2020) and ClinicalTrials.gov systematic literature search using the following terms: blinatumomab, Blincyto, lymphoblastic leukemia, and bispecific T-cell engager. Study Selection and Data Extraction: All relevant published articles, package inserts, and meeting abstracts evaluating the use of blinatumomab in ALL were considered for inclusion. Data Synthesis: Blinatumomab, a first-in-class bispecific T-cell engager monoclonal antibody, facilitates cytotoxic T-cell activation and subsequent eradication of CD19-positive B cells. The confirmatory phase III TOWER trial demonstrated superior overall survival (OS) with blinatumomab compared with standard chemotherapy (7.7 months vs 4.0 months) in relapsed and refractory (R/R) B-cell ALL. In the phase II BLAST trial, blinatumomab achieved a complete measurable residual disease (MRD) response in 78% of evaluable patients, with a median OS of 36.5 months. Potentially life-threatening cytokine release syndrome and neurotoxicity occurred in approximately 15% and 65% of patients, respectively. Relevance to Patient Care and Clinical Practice: Following initial Food and Drug Administration approval in 2014, blinatumomab gained expanded approval in pediatric patients and in Philadelphia chromosome-positive R/R ALL. In 2018, blinatumomab became the first and only drug approved for the treatment of persistent MRD in any hematologic malignancy. Emerging data demonstrate promising efficacy with blinatumomab in specific ALL settings, including frontline therapy, as a bridge to transplantation, and in “chemotherapy-free” combination regimens. Conclusions: Blinatumomab provides a paradigm-shifting treatment option; however, many questions surrounding optimal patient selection, sequencing, and cost-effectiveness remain.

T-Cell activation by t(9;22) acute lymphoblastic leukemia-derived dendritic-like cells is associated with increased tapasin expression

2005 ◽  
Vol 55 (2) ◽  
pp. 160-165 ◽  
Author(s):  
Jonathan A. Claus ◽  
Michael T. Brady ◽  
Jaewoo Lee ◽  
Kathleen A. Donohue ◽  
Sheila N. Sait ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphoblastic Leukemia

Detection of HTLV1 in Patients with B and T-Cell Malignancies Which Are Different to Adult T-Cell Leukemia-Lymphoma: A Prospective Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3869-3869
Author(s):  
Jose J.M. Marquez ◽  
Natalia N.O. Ortiz ◽  
Ramon R.C. Cisterna ◽  
Jose Maria J.B. Beltran de Heredia
Keyword(s):  
T Cell ◽  
B Cell ◽  
Virus Type ◽  
T Cell Activation ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Hla Dq

Abstract Human T-lymphotropic virus type I (HTLV-I), is the pathogenic agent of adult T-cell leukemia-lymphoma (ATLL), which always shows monoclonal HTLV-I provirus DNA integration. HTLV-I is rarely associated with B-cell disorders. The gen Tax of a human T-cell leukemia virus type I (HTLV-I) induces the expression of several cellular genes that are involved in T cell activation and proliferation. In the current study was to analyze prospectively HTLV-I proviral DNA presence in peripheral blood mononuclear cells (PBMCs) in patients with leukemia or lymphoma which are different to ATLL. Following this pattern we have studied in 61 patients with T and B-cell malignancies the presence of the virus HTLV-I on the during our service between April 2004 and May 2006. A real time PCR assay using SYBR Green intercalation was established. Primer and hybridization probes targeting tax region were standardized against MT2 cell line DNA for HTLV-I. The assay reliably detected a single copy of HTLV-I proviral genome in DNA from 1X106 PBMCs. Also included for each sample the HLA-DQ alpha gene (a measure of genomic DNA), We have detected the presence of HTLV-I in five patients: 2 patients with B-CLL (lymphocytes count: 1.3 x 109/L and 16,8 respectly), one patient with T-ALL CD4 and CD8 positive; other with NHL and one with B-ALL Ph+. As an interesting data, one of the patients with B-CLL presented as complication a immune thrombocytopenia after Fludarabine therapy. Two patients were died and the two cases with B-CLL show stable sickness. Only the patient with T-ALL achieved complete remission after chemotherapy. In conclusion, we have detected on our series, in a unsuspected way, the presence of HTLV-I on some of the patients with lymphoid malignancies, which are different to the ATLL, showing in these cases an atypical clinic course. After knowing the repercussion of HTLV-I over the immune competition of the infected patients it seems suggestive speculate on the possible implication of the virus in a deterioration of the immunity favouring the progress of neoplasia and/or a greater propensity to infections and immunological upheavals, like the observed ones in our series.

Immunopharmacodynamic response to blinatumomab in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7020-7020 ◽  
Author(s):  
Andrea Schub ◽  
Virginie Nägele ◽  
Gerhard Zugmaier ◽  
Christian Brandl ◽  
Youssef Hijazi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphoblastic Leukemia ◽  
Granzyme B ◽  
Significant Proportion ◽  
Target Cells ◽  
Cell Counts

7020 Background: Blinatumomab is an anti-CD19/anti-CD3 bispecific T cell engager (BiTE) that induces target cell-dependent, polyclonal T cell activation and proliferation, resulting in redirected lysis of CD19+ target cells. Methods: In a phase 2 study, adult patients (N=36) with relapsed/refractory B-precursor ALL received continuous blinatumomab IV infusion for 28 days in ≤5 treatment/consolidation cycles. Whole blood and serum samples were collected throughout treatment and analyzed for lymphocyte subpopulations, cytokines, granzyme B, and blinatumomab serum concentrations. Results: Lymphocytes in all patients responded in a similar fashion. After infusion start, peripheral B cell counts dropped to ≤1 B cell/μL in <1 week and remained undetectable throughout treatment. Peripheral T cells showed a redistribution characterized by swift disappearance within the first 2-6 hrs and subsequent recovery to baseline within several days. Otherwise, T cell counts remained at least stable in most patients. In some patients even an expansion of the T cell compartments was observed, most likely due to specific proliferation of activated T cells but could not be defined as prerequisite for treatment efficacy. During the first infusion days, a significant proportion of T cells newly expressed the activation marker CD69, and the T cell effector molecule granzyme B was detectable in serum. Additionally, a transient cytokine release dominated by IL-10, IL-6 and IFN-γ was observed in most patients shortly after first infusion start, which was alleviated or absent in subsequent cycles. Blinatumomab serum steady state concentrations (mean±SD) were 198±61 pg/mL and 694±236 pg/mL at doses of 5 and 15 μg/m²/d, respectively, which is comparable to those from previous studies. Conclusions: Immunopharmacodynamic response to blinatumomab was characterized by B cell depletion, T cell activation and redistribution, and release of granzyme B and cytokines, suggesting T cell engagement according to the expected BiTE mode of action. The tested pharmacodynamic markers did not allow for predictive differentiation between patients achieving a hematologic response and those who did not. Clinical trial information: NCT01209286.

A phase I/II study of blinatumomab in combination with pembrolizumab for adults with relapsed refractory B-lineage acute lymphoblastic leukemia: University of California Hematologic Malignancies Consortium Study 1504.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7064-TPS7064 ◽  
Author(s):  
Marc Saul Schwartz ◽  
Deepa Jeyakumar ◽  
Lloyd Earl Damon ◽  
Gary J. Schiller ◽  
Matthew Joseph Wieduwilt
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Phase I ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphoblastic Leukemia ◽  
Multicenter Trial ◽  
Response To Therapy ◽  
Phase Iii

TPS7064 Background: Outcomes for adults with relapsed/refractory B-cell ALL (R/R B-ALL) remain poor despite new targeted therapies. Blinatumomab is an anti-CD19/CD3 bifunctional T-cell engaging antibody that was superior to conventional salvage therapy for remission and overall survival in a Phase III study of patients with R/R B-ALL. The CR/CRh rate for blinatumomab was 65.5% with < 50% marrow lymphoblasts but dropped to 34.4% with ≥ 50% marrow lymphoblasts. Clinical and pre-clinical findings suggest that PD-L1 overexpression on lymphoblasts and in the bone marrow may mediate resistance to blinatumomab by inhibiting T-cell activation. We hypothesize that addition of pembrolizumab will improve CR/CRh rates to blinatumomab in R/R B-cell ALL. Methods: We are conducting a phase I/II multicenter trial to evaluate the safety and efficacy of blinatumomab with pembrolizumab in adults with R/R B-ALL and a high bone marrow lymphoblast percentage (NCT 03160079). The primary endpoint is ORR (CR+CRh) after 1-2 cycles with secondary endpoints of AEs, MRD-negative CR/CRh rate, 2-year DFS, 2-year OS, and allogeneic HCT rate. Exploratory studies are evaluating cytokine expression, PD-1 expression on T-cells, PD-L1 and PD-L2 protein expression on lymphoblasts, and T-cell populations at diagnosis and in response to therapy. Eligibility includes: adults with R/R CD19+ B-ALL after ≥ 1 prior line of therapy, R/R Ph+ B-ALL must fail a 2nd- or 3rd-generation TKI or be TKI intolerant, > 50% lymphoblasts on screening bone marrow sample. Blinatumomab is given by continuous IV at 9 mcg/day days 1-7 of cycle 1, 28 mcg/day days 8-28 of cycle 1, then at 28 mcg/day days 1-28 in subsequent cycles. Pembrolizumab 200 mg IV is given on days 15 and 36 of each 42-day cycle. Patients in CR/CRh after 1-2 cycles will complete 5 cycles. Patients not in CR/CRh after 2 cycles of therapy or progressing after Day 15 of cycle 1 go off study. CNS prophylaxis with IT methotrexate is given at screening and once per cycle. A phase I run-in of 3-6 patients precedes accrual of 18-21 patients for a target of 24. The study opened in July 2017 and 4 patients have been treated. No DLTs have occurred to date. Clinical trial information: NCT03160079.

scholarly journals Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia

Blood ◽  
2017 ◽  
Vol 130 (21) ◽  
pp. 2326-2338 ◽  
Author(s):  
Regina Wan Ju Wong ◽  
Phuong Cao Thi Ngoc ◽  
Wei Zhong Leong ◽  
Alice Wei Yee Yam ◽  
Tinghu Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
T Cell Activation ◽  
Gene Expression Analysis ◽  
Cell Activation ◽  
Leukemia Cells ◽  
Cancer Genes ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Key Points

Key Points Enhancer profiling combined with gene expression analysis identifies CCR4 and TIAM2 as critical cancer genes in ATL. Super-enhancers are enriched at genes involved in the T-cell activation pathway in ATL, reflecting the origin of leukemia cells.

T Cell Activation by t(9;22) Acute Lymphoblastic Leukemia-Derived Dendritic-Like Cells Is Associated with Increased Expression of Antigen Processing Machinery Components.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4301-4301
Author(s):  
Jonathan A. Claus ◽  
Michael A. Brady ◽  
Jaewoo Lee ◽  
Kathleen A. Donohue ◽  
Soldano Ferrone ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
T Cell Activation ◽  
Antigen Processing ◽  
Cell Activation ◽  
Lymphoblastic Leukemia ◽  
Hla Class I ◽  
Antigen Expression ◽  
Antigen Processing Machinery ◽  
Processing Machinery

Abstract We have recently shown that dendritic-like cells derived from t(9;22) acute lymphoblastic leukemia (ALL) cells can activate T cells, while the original unmodified leukemic blasts cannot. To define the molecular basis of this functional difference, we have compared the level of antigen processing machinery components in unmodified blasts and ALL-derived dendritic-like cells, since they play a major role in antigen presentation. Six patient samples and one t(9;22) ALL cell line (Z119) were studied. Dendritic-like cells were generated by in vitro culture with CD40 ligand, interleukin (IL)-1β, IL-3, IL-7, stem cell factor and tumor necrosis factor-α for six days. Maturation was verified by morphology and CD80/CD86 expression. Cells were studied for HLA class I and class II antigen expression. Furthermore, antigen processing machinery component expression was analyzed by intracellular staining with a unique panel of monoclonal antibodies which recognize the constitutive proteasome (Z, MB1, delta) and immunoproteasome (LMP2, LMP7, LMP10) subunits, the transporter subunits TAP 1 and 2 and the chaperones calnexin, ERp57, calreticulin and tapasin. HLA Class I antigen and HLA-DR/DQ/DP antigen expression was significantly up-regulated on the dendritic-like cells. LMP2, LMP7 and tapasin expression was significantly up-regulated in all t(9;22) ALL-derived dendritic-like cells, in comparison to the unmodified blasts. No significant difference was detected in the expression of the other antigen processing machinery components. These results suggest that T cell activation by t(9;22) ALL-derived dendritic-like cells is associated with increased expression of some, but not all, of the antigen processing machinery components. Whether t(9;22) ALL-derived dendritic-like cells can be used as a cellular vaccine for adoptive immunotherapy of ALL is being investigated.

scholarly journals Resting and anergic B cells are defective in CD28-dependent costimulation of naive CD4+ T cells.

1994 ◽  
Vol 179 (5) ◽  
pp. 1539-1549 ◽  
Author(s):  
W Y Ho ◽  
M P Cooke ◽  
C C Goodnow ◽  
M M Davis
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cell Antigen ◽  
Naïve T Cells ◽  
Activation Antigens

Successful antibody production in vivo depends on a number of cellular events, one of the most important of these being cognate B cell-T cell interaction. To examine this phenomenon in vitro, homogeneous populations of hen egg lysozyme (HEL)-specific small resting B cells and naive CD4+ HEL-specific T cells (derived from immunoglobulin [Ig] and T cell receptor transgenic mice, respectively) were cultured together. On addition of intact HEL protein. HEL-specific B cells increase their expression of activation molecules, including a B7-related protein and CD44, and enlarge into blast cells. Within the same cultures, HEL-specific CD4+ T cells also increase expression of the activation markers CD69 and CD44, enlarge, secrete lymphokines, and proliferate. This response is radiation sensitive, supporting the conclusion that HEL-specific B cells present antigen to and activate the naive T cells. By contrast, when a synthetic peptide fragment of HEL is used to bypass B cell antigen-receptor engagement, the naive T cells enlarge and display activation antigens, but fail to produce lymphokines, proliferate, or promote B cell blastogenesis. Presentation of HEL by tolerant B cells, which are no longer able to signal effectively through their antigen receptors, results in an identical pattern of incomplete T cell activation. Addition of a stimulating anti-CD28 antibody and blocking of CD28 signals with CTLA4/Ig fusion protein both show that complete activation of naive CD4+ T cells depends on the initial induction of B7 and related costimulatory molecules after HEL binding to nontolerant HEL-specific B cells. Thus, in the absence of adequate constimulation from the B cell, naive CD4+ T cells undergo a form of "partial activation" in which they upregulate surface expression of certain T cell activation antigens, but fail to efficiently produce lymphokine and proliferate. This may explain the different conclusions that have been reached regarding the consequences of B cell antigen presentation to T cells, in that the ability of B cells to activate naive CD4+ T cells depends both on their specificity and their activation state.

Sign in / Sign up

Export Citation Format

Share Document